Modified artery-first approach for distal pancreatectomy with celiac axis resection

Abstract Background The superior mesenteric artery-first approach has been proved superior in pancreatoduodenectomy compared with the standard procedure. It is unclear whether similar benefits could be obtained in distal pancreatectomy with celiac axis resection. Methods Perioperative and survival outcomes of patients who underwent distal pancreatectomy with celiac axis resection with the modified artery-first approach or traditional approach between January 2012 and September 2021 were compared. Results The entire cohort comprised 106 patients (modified artery-first approach, n = 35; traditional approach, n = 71). The most common complication was postoperative pancreatic fistula (n = 18, 17.0 per cent), followed by ischaemic complications (n = 17, 16.0 per cent) and surgical site infection (n = 15, 14.0 per cent). Intraoperative blood loss (400 versus 600 ml, P = 0.017) and intraoperative transfusion rate (8.6 versus 29.6 per cent, P = 0.015) were lower in the modified artery-first approach group compared with the traditional approach group. A higher number of harvested lymph nodes (18 versus 13, P = 0.030) and R0 resection rate (88.6 versus 70.4 per cent, P = 0.038) and a lower incidence of ischaemic complications (5.7 versus 21.1 per cent, P = 0.042) was observed in the modified artery-first approach group compared with the traditional approach group. In multivariable analysis, the modified artery-first approach (OR 0.006, 95 per cent c.i., 0 to 0.447; P = 0.020) was protective against ischaemic complications. Conclusions Compared with the traditional approach, the modified artery-first approach was associated with lower blood loss and fewer ischaemic complications, and a higher number of harvested lymph nodes and R0 resection rate. Thus, it might improve the safety, staging and prognosis of distal pancreatectomy with celiac axis resection for pancreatic cancer.


Introduction
Pancreatic cancer is an aggressive disease expected to become the second leading cause of cancer death within the next 10 years 1,2 . Surgical resection offers a curative chance for pancreatic cancer patients, but more than 80 per cent of those are not suitable for resection at the time of diagnosis 3 . Lesions of the pancreas body/tail with involvement of the celiac axis (CA) > 180° are considered locally advanced 4 . Those lesions, when the aorta and/or the gastroduodenal artery (GDA) are not involved, can be radically resected through distal pancreatectomy with celiac axis resection (DP-CAR), especially if induction chemotherapy is administrated prior to surgery. DP-CAR is a challenging procedure. Local radicality is difficult to achieve in locally advanced pancreatic cancer (LAPC) due to significant invasion of retroperitoneal tissues. Previous international multicentre studies reported an R0 resection rate of 54-59 per cent 5,6 . DP-CAR is associated with a high morbidity rate and a 90-day mortality rate as high as 16-18 per cent 5,6 .
According to previous studies 6 , ischaemic complications of DP-CAR account for one-third of the 90-day mortality rate and cannot be prevented by existing strategies. Considering these limitations, appropriate preoperative patient selection may avoid DP-CAR in patients who may not benefit from it 6,7 . Similarly, it is crucial to determine whether DP-CAR is applicable in the early phase of the operation.
The superior mesenteric artery-first approach was proposed to determine arterial involvement prior to pancreas transection during pancreatoduodenectomy 8,9 . The same concept can be applied to CA and DP. The aim of the present study is to compare the modified artery-first approach (mAFA) for DP-CAR to the traditional approach (TA) in terms of postoperative and long-term outcomes. and September 2021. Patients' data was retrospectively retrieved from the Changhai prospective database of pancreatic tumours. The project was approved by the Changhai Hospital Ethics Committee (CHEC2021-140).

Preoperative evaluation
Preoperative assessments included medical history, physical examination, laboratory testing and contrast-enhanced computed tomography. Since 2016, most patients received at least three cycles of neoadjuvant therapy (NAT), and the NAT regime was decided by the attending doctor. The indications for DP-CAR were discussed in a multidisciplinary meeting and included tumour of the pancreatic body/tail with involvement of the common hepatic artery (CHA) and/or CA, and without involvement of the superior mesenteric artery (SMA), proper hepatic artery (PHA), GDA or distant metastasis.

Surgical technique
Step 1. Exploration and GDA backflow assessment The abdomen was opened preferably through a midline incision and the absence of distant metastasis was confirmed.

mAFA group
The first step included a wide Kocher's manoeuvre and dissection of the soft tissues along the CA and SMA. A vessel loop was used to wrap the roots of CA and SMA (Fig. 1a, c). After clamping the CA root, dissection of the CHA was performed, the CHA was then temporarily clamped (Fig. 1b) and the blood flow of the PHA and right gastroepiploic artery (RGA) was assessed using ultrasonography and/or palpation. If the blood flow was considered sufficient, the CHA was ligated. Otherwise, the DP-CAR procedure was abandoned, and radical antegrade modular pancreatosplenectomy (RAMPS) 10 with arterial divestment or a palliative procedure was performed, according to the severity of arterial infiltration.
TA group TA has been previously described 11,12 . The Kocher's manoeuvre was not performed in this group. The first step included assessment of the backflow in the GDA clamping the CHA. The CA, instead, was isolated only after pancreatic neck transection.

Step 2. Pancreatic transection and perivascular clearance
The pancreas was transected using a linear stapler. If the tumour was too close to the bifurcation of GDA and PHA and it was not possible to use a linear stapler, GDA was separated from the pancreas by cold dissection, the pancreas was transected with a scalpel and a hand-sewn closure was used for the pancreatic stump. The splenic vein was dissected and ligated. Superior mesenteric vein (SMV)/portal vein (PV) resection and reconstruction were performed if required. To achieve local radicality, the SMA was skeletonized. CA was ligated at its origin. The soft tissue between SMA, CA and SMV/PV was removed.

Step 3. En bloc resection of the tumour and retropancreatic tissues
To perform complete retropancreatic dissection, the RAMPS method 10 was used. In most cases, the Gerota's fascia was cut, and the anterior aspect of the para-renal fat and the pancreatic body and tail, spleen and left adrenal gland were resected (Fig. 1d). A partial gastrectomy was performed if the stomach was involved.

Intra-and postoperative data
Surgical outcomes included blood loss volume, blood transfusion rate, and concomitant vein or stomach resection. Pathological data included tumour size, differentiation grade, number of positive lymph nodes and R0 resection rate. N staging was classified according to the 8th edition of the AJCC Cancer Staging Manual 13 . R0 resection was defined as a resection margin more than 1 mm away from the tumour 14 .
Postoperative pancreatic fistula (POPF) 15 , delayed gastric emptying (DGE) 16 and postpancreatectomy haemorrhage (PPH) 17 were defined according to the definitions proposed by the International Study Group (ISGPS). Grade B/C DGE was defined as clinically relevant DGE (CR-DGE). The severity of complications was graded using the Clavien-Dindo classification 18 . Major complications were defined as grade III or higher. Ischaemic complications included postoperative gastric or liver ischaemia, and other complications caused by insufficient arterial perfusion after DP-CAR. In particular, gastric ischaemia was defined as postoperative gastric dysfunction with endoscopic evidence of ischaemic findings (for example ulceration/necrosis) and/or gastric perforation identified by imaging or during reoperation. Liver ischaemia was defined as elevated alanine aminotransferase (ALT) (more than 500 IU/l) levels within 3 days after surgery. Postoperative liver function was tested on postoperative days 1 and 3. Overall survival (OS) was defined as the time from date of surgery to patient death. Follow-up ended in December 2021.

Statistical analysis
Data were analysed using SPSS 25.0. Categorical variables were expressed as absolute frequencies and percentages, and compared using the chi-square test or Fisher's exact test. Continuous variables were expressed as median with ranges and compared using the Mann-Whitney U test. To identify risk factors for ischaemic complications, preoperative and intraoperative variables were included in univariate/multivariate analyses based on the Akaike information criterion. Survival curves were constructed using the Kaplan-Meier method and assessed by log rank test, which was performed by GraphPad Prism 8.0. P < 0.05 were considered statistically significant.

Patient population
A total of 128 consecutive patients with pancreatic cancer of the body/tail involving the CA/CHA scheduled for DP-CAR were included (Fig. 2). Eight patients were excluded due to distant metastasis. For eight patients (10.1 per cent) in the TA group and four (9.8 per cent) in the mAFA group, DP-CAR was abandoned due to insufficient blood flow. Two patients (4.9 per cent) in the mAFA group were excluded due to SMA invasion. Overall, 106 patients underwent DP-CAR, 35 in the mAFA group and 71 in the TA group. Table 1 shows baseline characteristics. Some 29 patients (27.4 per cent) received preoperative NAT, with most patients receiving gemcitabine/abraxane (n = 21, 19.8 per cent). A significantly higher proportion of patients in the mAFA group (n = 25, 71.4 per cent) received NAT compared with the TA group (n = 4) (71.4 per cent versus 5.6 per cent, P < 0.001). Preoperatively, carbohydrate antigen 19-9 (CA 19-9; 54.8 versus 367.7 U/ml, P = 0.011) and carcinoembryonic antigen (CEA; 2.6 versus 3.7 U/ml, P = 0.035) levels were lower in the mAFA group. Preoperative liver function and routine blood tests were similar between the two groups.

Operative characteristics and pathological findings
The median operative time for the overall cohort was 137.5 min, with no significant difference between the mAFA and TA groups (130 versus 140 min, P = 0.448). The mAFA group had less intraoperative blood loss compared with the TA group (400 versus 600 ml, P = 0.017) and the intraoperative transfusion rate was lower (n = 3, 8.6 per cent versus n = 21, 29.6 per cent, P = 0.015). Some 15 (14.2 per cent) underwent SMV/PV resection, while 7 (6.6 per cent) underwent partial gastrectomy ( Table 2).
The median tumour diameter was 4.2 cm. All tumours were poorly (n = 20, 18.9 per cent) or moderately (n = 86, 81.1 per cent) differentiated. A higher number of lymph nodes were harvested in the mAFA group compared with the TA group (18.0 versus 13.0, P = 0.030). There was no significant difference between the two groups in terms of N stage, lymphovascular invasion and perineural invasion. The R0 resection rate was higher in the mAFA group than in the TA group (n = 31, 88.6 per cent versus n = 50, 70.4 per cent, P = 0.038).

Operative outcomes
The most common complication of DP-CAR was POPF (n = 18, 17.0 per cent), followed by ischaemic complications (n = 17, 16.0 per cent) and surgical site infections (n = 15, 14.2 per cent). Major complications occurred in 13 patients (12.3 per cent), and seven patients (6.6 per cent) were re-admitted to the hospital within 30 days after the operation. The incidence of complications, such as POPF, operative site infection and multiple organ dysfunction syndrome (MODS), was not significantly different between the two groups. Similarly, there was no statistical difference in major complications, reoperation rate and 30-day re-admission rate ( Table 3).
Postoperative liver function and routine blood tests were not significantly different between the two groups. The median duration of hospital stay was 8 days, with no significant difference between the groups (7 versus 9 days, P = 0.060). The two groups had similar hospitalization costs (7162.   complications was lower compared with the TA group (n = 2, 5.7 per cent versus n = 15, 21.1 per cent, P = 0.042). In the entire cohort, four patients (3.8 per cent) died within 90 days, all of whom were in the TA group. Deaths were in all cases directly or indirectly related to the ischaemic complications. One patient died due to MODS secondary to acute liver ischaemia 2 days after the surgery. The second patient developed bile leakage due to liver ischaemia, which aggravated POPF and resulted in fatal bleeding 2 weeks after surgery. The remaining two patients suffered gastric perforation and succumbed to severe sepsis almost 1 month after surgery. Except for the four patients mentioned above, the remaining 13 patients recovered from the ischaemic complications after symptomatic treatment. Univariable and multivariable analyses on factors associated with ischaemic complications are shown in Table S1. The mAFA technique, preoperative CA 19-9 and tumour size were associated with postoperative ischaemic complications in the univariable analysis. In the multivariable analysis, the mAFA (OR 0.006, 95 per cent c.i., 0-0.447; P = 0.020) was identified as an independent protective factor for ischaemic complications.
Discussion mAFA was associated with lower blood loss, fewer ischaemic complications, and a higher number of harvested lymph nodes and R0 resection rate. As previously described 19 , massive intraoperative blood loss is a striking feature of DP-CAR, which directly affects its surgical safety, increasing morbidity rate and mortality rate 20,21 . In the mAFA, the CA is clamped at an early phase of the operation, which could explain the lower blood losses described in this study compared with the literature. Ischaemic complications are typical of DP-CAR and they can have severe consequences, such as liver abscess, gastric perforation, sepsis and even death 22 . In the present study, the mAFA group had a lower incidence of ischaemic complications compared with the TA group, and the mAFA was protective against ischaemia in multivariable analysis. Furthermore, four patients in the TA group died of direct or indirect ischaemic complications, while no patient died of ischaemic complications in the mAFA group. This could be explained by an inaccurate assessment of collateral flow in the TA group. Indeed, in this approach, only the CHA is clamped at the beginning, while in the mAFA the CA is clamped at its origin allowing identification of potential perfusion alteration.
For LAPC patients, a typical location for R1 positive margins is in proximity of the SMA and CA 23,24 . In the present study, mAFA achieved a higher rate of R0 resection and detected a higher number of lymph nodes compared with the TA, improving local radicality and quality of DP-CAR. Although the survival analysis showed no significant difference between the groups, this could be explained by the relatively small numbers. It should be noted that a higher percentage of patients in the mAFA group were treated with NAT than the TA group, which may affect the comparison of R0 resection and survival rate between the two groups.
The present study had some limitations. The retrospective nature of the study limits the robustness of the comparison. A 10-year time span might have introduced time-dependent bias. For example, NAT was widely used after 2016 and therefore more patients in the mAFA group underwent NAT. The mAFA described in this study is derived from a high-volume centre with over 1000 pancreatectomies per year, and it is unclear whether similar benefits could also be obtained in low-volume centres. A recent multicentre study 6 suggested that the 90-day mortality rate in low-volume DP-CAR centres was about three-fold higher than that in high-volume centres (18.0 per cent versus 5.5 per cent, P = 0.015). Considering the underlying volume-outcome curve for this complex procedure, patients scheduled for DP-CAR should be centralized.
The mAFA technique was proposed to evaluate the root of CA/ SMA early in DP-CAR. Clamping of the CA root at the beginning of the operation reduced blood loss and allowed identification of patients at high risk of ischaemic complications. mAFA should be performed in high-volume pancreatic surgery centres to improve safety, staging and prognosis of DP-CAR for pancreatic cancer.

Disclosure
The authors declare no conflict of interest.

Supplementary material
Supplementary material is available at BJS Open online.

Data availability
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding authors.